ANN ARBOR, MI - Today's announcement that Celebrex, a popular pain drug in the same family as Vioxx, has been found to pose an increased risk of heart problems is bound to leave many pain patients stunned, confused and worried.

The Celebrex news comes just one week after the Food & Drug Administration required the manufacturer of Bextra, another drug in the same family of Cox-II medications, to warn patients of a heart risk associated with that medication.

And of course, Vioxx has been off the market since October, when it was pulled because of mounting evidence that it carried heart risks.

Now, with a shadow cast over the entire Cox-II family of drugs, a University of Michigan expert offers advice for patients who have been taking Celebrex or Bextra, or who stopped taking Vioxx and still aren't sure which drug to choose for pain relief.

“In light of this discouraging news, individuals who are taking either Celebrex or Bextra should immediately contact their physician,” says Mark Fendrick, M.D., a U-M professor of internal medicine who has studied the use of the family of medicines that includes the Cox-IIs, known as non-steroidal anti-inflammatory drugs or NSAIDs.

“Even if these drugs remain on the market, given the availability of other therapies that provide equivalent levels of pain relief and stomach protection, it would be prudent to avoid Celebrex and Bextra until we know for sure about their cardiovascular safety,” Fendrick adds.

The choice may come down to letting your heart or your gut decide – literally. Patients should be treated with medications based in part on their individual risks for heart disease and stomach problems, says Fendrick.

He recently published a pain-medication guideline for doctors that was published in the November issue of the American Journal of Managed Care.

This guideline takes into account the evidence that Vioxx and its cousins likely raise the risk of a heart attack.

“Every patient is different, but there are clear options even in the wake of the Vioxx situation,” says Fendrick. “Patients should work with their clinicians to determine the best combination for them, and to persist until they get relief. No one should have to live with pain and other symptoms that interfere with their daily life.”

Fendrick's guide for treating patients' pain can be boiled down into a four-box grid that takes into account risk for heart disease and risk for gastrointestinal problems caused by NSAIDs. (see below)

It's based on research showing that Cox-II drugs or “superaspirins”, can ease pain just as well as – but no better than - other NSAIDs. But Cox-II inhibitors may carry a lower risk of ulcers or of bleeding in the digestive tract than the more traditional NSAIDs, such as ibuprofen or naproxen.

Traditional NSAIDs are available both by prescription and over-the-counter in stores. But either way, they're much less expensive than Cox-II inhibitors.

The grid also takes into account the fact that many people take another NSAID — aspirin — every day to reduce their risk of a heart attack. Taking aspirin with any other NSAID, including Cox-II inhibitors, creates a combined effect that markedly increases the risk of gastrointestinal complication including ulcers and bleeding.

“Most patients and many clinicians are unaware of the fact that adding aspirin to a Cox II inhibitor takes away a great deal, if not all, of the gastrointestinal safety benefit,” says Fendrick. “In fact, a recent national study showed that over 50 percent of Cox II users also take aspirin, and are therefore putting themselves at risk for ulcers and gastrointestinal bleeding.”

Add to that the added heart risk that Cox-II inhibitors appear to carry, and it turns out that people who have suffered heart attacks, chest pains or strokes, or have a high risk for them, probably shouldn't take Cox II drugs at all.

But many patients who take NSAIDs may get benefit by adding a stomach-protecting drug called an acid blocker, or proton pump inhibitor. These are available by prescription (under the names Nexium and Prevacid) or over the counter (sold as Prilosec).

“So, the bottom line is, patients should talk with their clinicians about their pain, their heart risk, and their risk factors for gastrointestinal complication from NSAIDs. Don't assume that what works for one person will work for you, or that risks or side effects are the same for everyone,” says Fendrick. “And no matter what, be frank with your doctor about pain that you're feeling, because in the end you should be able to get relief.”

Pain Medication Grid:

Choose the box that corresponds to your particular heart (left column) and gut (top row) situation.

Important note: ALL patients should talk to their clinicians about these general guidelines to decide what drugs are right for them and what dose to take!

Written by Kara Gavin

Message to U-M physicians - Sent by the Faculty Group Practice, Dec. 20, 2004

Valdecoxib (Bextra) and Celecoxib (Celebrex) have recently been reported to be associated with increased risk of cardiovascular events. The most recent data are from several randomized placebo-controlled studies. Based on these reports:

• VALDECOXIB (Bextra) should NOT be used in patients with pre-existing cardiac conditions.
• VALDECOXIB (Bextra) and CELECOXIB (Celebrex) should be used with extreme caution in patients at increased risk of cardiovascular events.
• Recent data with CELECOXIB (Celebrex) suggest that special caution should be used in patients receiving 400 mg per day or more.

We have been asked how the UMHS system should respond to this news - in the material below we address:

• What are these recommendations based on?
• What recommendations should be given to patients on these medications?
• Is this a class effect or drug effect?
• Where can I get more information?

What is the Valdecoxib (Bextra) recommendation based on?
A recently-completed study conducted by Pfizer, which included over 1,500 patients treated after CABG, showed that patients treated with Valdecoxib (Bextra) had twice the risk of a cardiovascular event compared to those treated with placebo (1% vs. 0.5%).

What is the Celecoxib (Celebrex) recommendation based on?
In the Adenoma Prevention with Celecoxib (APC) trial, patients taking 400mg and 800mg of Celebrex daily had an approximately 2.5 fold increase in their risk of experiencing a cardiovascular event compared to those patients taking placebo. Cardiovascular event rates were higher in those taking 800mg compared to 400mg daily. Based on these findings, the sponsor of the trial, the NCI, has suspended the dosing of Celebrex in the study.

Of note, in the Prevention of Spontaneous Adenomatopus Polyps (PreSAP) trial, there has been no increased risk for Celebrex patients taking 400mg daily compared with those taking placebo. These findings are based on an identical analysis used to assess cardiovascular risk in the APC trial and conducted by the same independent safety review board. The two studies, which are following patients over a five-year period, have enrolled 3,600 patients thus far.

Pfizer, after discussions with the FDA, has stopped all direct-to-consumer advertising for celecoxib.

What recommendations should be given to patients?
Patients with known coronary artery disease would probably benefit from discontinuing these medications with guidance from their physicians. If patients ask what is their risk of continuing to take the medication the FDA has previously stated that for rofecoxib "the risk that an individual patient [taking Vioxx] will suffer a heart attack or stroke related to the drug is very small." For patients with significant risk factors for coronary artery disease, we recommend that alternative medications be considered for their symptoms. Patients on valdecoxib (Bextra) or celecoxib (Celebrex) may either be switched to acetaminophen or a traditional non-steroidal anti-inflammatory drug (NSAID). Acetaminophen, up to four grams daily, provides similar pain relief for many patients with osteoarthritis and should be considered before beginning an NSAID. If acetaminophen is not successful or an option then:

• If your patient is on or needs aspirin do not use a COX-2 agent as there is no additional safety benefit. Similarly, if a patient has increased risk for cardiovascular events do not use COX2 agents due to the recently reported increased incidence of cardiovascular events. We also recommend that you do not prescribe ibuprofen for patients requiring aspirin due to interference with aspirin's anti-platelet activity. Such patients may be prescribed naproxen.
• If your patient is on a gastroprotective agent regularly (i.e., a proton pump inhibitor or misoprostol), consider using a traditional NSAID as RCT data show similar complication rates for a traditional NSAID + Gastroprotective agent as for a COX-2 inhibitor.
• If your patient has a significant increased risk of a GI event (e.g., age > 60, past history of a gastric or duodenal ulcer, or on coumadin) and is not at increased risk for cardivascular events, then consider using a traditional NSAID with a gastroprotective agent, or a COX-2 agent if you and your patient believe this is the best option. Acetaminophen is still the safest choice for these high risk patients.
• If your patient has a significant increased risk of a GI event and is at increased risk for cardiovascular events, then consider a traditional NSAID + gastroprotective agent or using other classes of medications (e.g., acetaminophen or low dose narcotics).

Is this class effect (COX-2 agents) or drug effect (rofecoxib)?
While the answer remains unknown, the newest information indicates that this may be a class effect. A series of four studies has shown the increased risk of cardiovascular events with rofecoxib (Vioxx). Similar results have now been reported for both celecoxib (Celebrex) and valdecoxib (Bextra), the two other COX-2 agents available in the United States.

Where can I get more information?
More information on this market withdrawal may be found at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#Bextra and http://www.pfizer.com/are/investors_releases/2004pr/mn_2004_1217.cfm
Please contact the Drug Information Service, 936-8200, should you have any questions regarding this information.

This FGP Gram was prepared by Steven J. Bernstein, MD with assistance from Pharmacy Services. Questions or comments about this FGP Gram may be directed to iCARE@umich.edu or Lisa Wehr, PharmD at luba@umich.edu. Feedback about any FGP Gram is always appreciated.

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